title: Activation of central angiotensin type 2 receptors suppresses norepinephrine excretion and blood pressure in conscious rats.
abstract: BACKGROUND
  We have previously documented the finding that central angiotensin type 2 receptors (AT2R) negatively modulate sympathetic outflow and arterial blood pressure (BP). In this study, we investigated the effects of intracerebroventricular (icv) infusion of Compound 21 (C21), the first selective nonpeptide AT2R agonist, on norepinephrine (NE) excretion and BP in rats.
  
  
  METHODS
  C21 was infused icv for 7 days, using a micro-osmotic pump. Urinary NE concentration was measured using the NE enzyme immunoassay kit. BP was recorded by radiotelemetry. After 7 days, the rats were killed and three relevant samples from sympathetic brain regions and the cerebral cortex were obtained by micro-punching to measure neuronal nitric oxide synthase (nNOS) protein expression by western blot. In addition, the influence of C21 on neuronal potassium current (I(Kv)) was determined by whole-cell patch-clamp in a neuron cell line, CATH.a.
  
  
  RESULTS
  (i) Icv treatment with C21 significantly decreased both the concentration and the amount of NE in night time urine, but had no effect on daytime urine. (ii) C21-treated rats exhibited a slight but significant decrease in BP. (iii) The effects of C21 on NE excretion and BP were abolished by use of the AT2R antagonist, PD123319, and nitric oxide synthase (NOS) inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME). (iv) C21 treatment significantly upregulated nNOS expression in the paraventricular nucleus of the hypothalamus (PVN) and rostral ventrolateral medulla (RVLM), but not in the nucleus of the solitary tract (NTS) and cerebral cortex. (v) In CATH.a neurons, C21 treatment significantly increased I(Kv), and this increase was completely abolished by PD123319 and L-NAME.
  
  
  CONCLUSIONS
  These results demonstrate a central inhibitory influence of C21 on sympathetic outflow by means of a nNOS-dependent mechanism that might be mediated by facilitating the neuronal potassium channel.
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Gao
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Khang D
authors.initials: KD
authors.lastname: Le
authors.forename: Jie
authors.initials: J
authors.lastname: Chao
authors.forename: Lie
authors.initials: L
authors.lastname: Gao
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D009474:Neurons / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis; D009638:Norepinephrine / Q000652:urine*; D011188:Potassium / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D007093:Imidazoles; D052248:Nitric Oxide Synthase Type I; D009638:Norepinephrine; D011188:Potassium; D011725:Pyridines; D044139:Receptor, Angiotensin, Type 2; D013449:Sulfonamides; C517061:N-butyloxycarbonyl-2-(4-imidazol-1-ylmethylphenyl)-4-butoxybenzenesulfonamide; D000096926:Benzenesulfonamides; C073402:PD 123319